Project 5 Patients with non-small cell lung cancer (NSCLC) and pleural spread have a median survival of 6 to 9 months which is similar to patients with distant metastatic spread. An exploratory trial of PhotofrinQmediated PDT in patients with NSCLC and pleural spread has recently demonstrated excellent local control and a median survival of 22 months. In this application, we propose to evaluate further pleural PDT for NSCLC and conduct studies that will lead to optimization of this approach. The specific aims of this project are to 1) to perform a Phase II clinical trial of intrapleural Photofrin-mediated PDT in patients with stage 1MB NSCLC defined by pleural dissemination 2) to assess Photofrin levels and tumor oxygenation in tumor from patients with NSCLC and assess PDT-induced changes in molecular signaling pathways, 3) to optimize a murine model of NSCLC pleural carcinomatosis and characterize the molecular consequences of PDT and 4) to develop new strategies for light delivery and light production that can be translated into future clinical studies. The significance of the clinical study is, if the preliminary clinical results are confirmed, then a novel therapeutic approach would be available for a patient population which has a poor prognosis. The correlative studies of PhotofrinD uptake and hypoxia and the characterization of signaling pathway response to PDT in preclinical models and human tissues will be used in future studies to develop ways to improve the therapeutic index for pleural PDT.